한국인을 대상으로 실시된 전장유전체 연관성 분석연구자료를 통한 요산전달체의 단일뉴클레오티드 다형태 빈도 및 요산과의 연관성 연구

Abstract

Objectives: Gouty arthritis is characterized by hyperuricemia, which results from overproduction of, or impaired renal excretion of, uric acid. Recently, interest has increased in renal urate transporters, which control the excretion of uric acid. Genome-wide association studies (GWASs) are now identifying risk alleles among renal urate transporter genes. At present, few studies of factors affecting uric acid regulation have been conducted on Koreans. We therefore aimed, first, to investigate the minor allele frequencies (MAFs) of single nucleotide polymorphisms (SNPs) associated with serum uric acid (SUA) level in the Korean population, and compare these with data from other ethnic groups (Study 1). Second, to investigate whether the SNPs are associated with altered SUA levels (Study 2).

Materials and Methods: 1. Study 1 1) Materials: We used datasets derived from two available GWASs. The first study was the Korean RA GWAS, including 800 rheumatoid arthritis (RA) cases and 757 controls, and the second was Korean systemic lupus erythematosus (SLE) GWAS, comprising 400 SLE cases (a total of 1957 subjects, Table 1). 2) Methods: We explored the GWAS results already obtained from subjects without gout to examine the frequencies of risk alleles, and investigated the MAFs of 40 previously described SNPs associated with SUA level in the Korean population, and compared results with data for other ethnic groups (Table 2). 2. Study 2 1) Materials: A total of 402 RA subjects satisfying the inclusion and exclusion criteria were selected from Study 1 (Table 3). 2) Methods: The representative value of SUA level in this study was determined by the highest value among SUA levels, obtained by searching the medical records of subjects in the GWAS from December 2000 to October 2012. Subjects with renal insufficiency of 60% or a low glomerular filtration rate (GFR), and serum creatinine levels exceeding 1.4 mg/dL as well as SLE patients were excluded. Also, we used the highest SUA values obtained before use of drugs that could increase SUA concentrations, such as antituberculosis medication. We analyzed associations with serum uric acid concentrations based on data from GWASs in the Korean population, and also tested whether polymorphism of any of the 40 SNPs associated with SUA identified previously were associated with SUA levels.

Results: 1. Study 1: We compared the MAFs of 13 SNPs in Koreans with those in other ethnic groups (Table 4). Overall, the MAFs of SNPs associated with SUA level in the Korean population were quite similar to those among Japanese, but not in populations of European descent. 2. Study 2: SNP rs12734001 (PPP1R12B) proved to have the most probable association with SUA concentrations (P_trend = 2.29 x 10-9) (Table 5). We also analyzed 13 SNPs shown previously by meta-analysis to be associated with SUA, and SNP rs3741414 (INHBC) was found to have their strongest association with SUA level observed in the present study (P_trend = 0.01) (Table 6).

Conclusions: The pattern of variants controlling SUA levels in the Korean population is quite similar to that in the Japanese population, but not in populations of European descent. SNP rs12734001 (PPP1R12B) is significantly associated with SUA level, and SNP rs3741414 (INHBC), previously identified SNP, is strongly associated with SUA levels among Koreans. In future, larger-scale studies and analyses of genes associated with SUA concentrations should be conducted in Korea.